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A [18F]Fluoroethoxybenzovesamicol Positron Emission Tomography Study

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A [18F]Fluoroethoxybenzovesamicol Positron Emission Tomography Study Received: 24 May 2018 Revised: 7 September 2018 Accepted: 10 September 2018 DOI: 10.1002/cne.24541 RESEARCH ARTICLE Regional vesicular acetylcholine transporter distribution in human brain: A [18F]fluoroethoxybenzovesamicol positron emission tomography study Roger L. Albin1,2,3,4 | Nicolaas I. Bohnen1,2,3,5 | Martijn L. T. M. Muller3,5 | William T. Dauer1,2,3,6 | Martin Sarter3,7 | Kirk A. Frey2,5 | Robert A. Koeppe3,5 1Neurology Service & GRECC, VAAAHS, Ann Arbor, Michigan Abstract 2Department of Neurology, University of Prior efforts to image cholinergic projections in human brain in vivo had significant technical lim- Michigan, Ann Arbor, Michigan itations. We used the vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxyben- 3University of Michigan Morris K. Udall Center zovesamicol ([18F]FEOBV) and positron emission tomography to determine the regional of Excellence for Research in Parkinson's distribution of VAChT binding sites in normal human brain. We studied 29 subjects (mean age Disease, Ann Arbor, Michigan 47 [range 20–81] years; 18 men; 11 women). [18F]FEOBV binding was highest in striatum, inter- 4Michigan Alzheimer Disease Center, Ann Arbor, Michigan mediate in the amygdala, hippocampal formation, thalamus, rostral brainstem, some cerebellar 18 5Department of Radiology, University of regions, and lower in other regions. Neocortical [ F]FEOBV binding was inhomogeneous with Michigan, Ann Arbor, Michigan relatively high binding in insula, BA24, BA25, BA27, BA28, BA34, BA35, pericentral cortex, and 6Department of Cell and Developmental lowest in BA17–19. Thalamic [18F]FEOBV binding was inhomogeneous with greatest binding in Biology, University of Michigan, Ann Arbor, the lateral geniculate nuclei and relatively high binding in medial and posterior thalamus. Cere- Michigan bellar cortical [18F]FEOBV binding was high in vermis and flocculus, and lower in the lateral cor- 7Department of Psychology, University of tices. Brainstem [18F]FEOBV binding was most prominent at the mesopontine junction, likely Michigan, Ann Arbor, Michigan associated with the pedunculopontine–laterodorsal tegmental complex. Significant [18F]FEOBV Correspondence Roger L. Albin, MD, 5023 BSRB, 109 Zina binding was present throughout the brainstem. Some regions, including the striatum, primary Pitcher Place, Ann Arbor, MI, 48109-2200, sensorimotor cortex, and anterior cingulate cortex exhibited age-related decreases in [18F] USA. FEOBV binding. These results are consistent with prior studies of cholinergic projections in Email: [email protected] other species and prior postmortem human studies. There is a distinctive pattern of human neo- Funding information Michael J. Fox Foundation for Parkinson's cortical VChAT expression. The patterns of thalamic and cerebellar cortical cholinergic terminal Research; NIH-NINDS, Grant/Award Number: distribution are likely unique to humans. Normal aging is associated with regionally specific P01 NS015655P50 NS091856R21 reductions in [18F]FEOBV binding in some cortical regions and the striatum. NS088302; Michael J. Fox Foundation KEYWORDS acetylcholine, aging, basal forebrain, cerebellum, pedunculopontine nucleus, RRID: SCR_001847, RRID: SCR_007037, striatum, thalamus 1 | INTRODUCTION Abbreviations: AC, anterior cingulate cortex; ACh, acetylcholine; AChase, ace- tylcholinesterase; AD, Alzheimer disease; AM, amygdala; BF, basal forebrain; Acetylcholine (ACh) is the primary neurotransmitter of several CNS ChAT, choline acetyltransferase; FEOBV, fluoroethoxybenzovesamicol; FL, floc- neuron populations. These include neurons of the basal forebrain culus; HIP, hippocampal formation; LG, lateral geniculate nucleus; MP, meso- (BF) complex projecting to numerous cortical regions, striatal choliner- pontine; MP4A, N-methyl-4-piperidyl acetate; MVC, medial vestibular complex; PD, Parkinson disease; PET, positron emission tomography; PMP, methyl- gic interneurons, the medial habenula–interpeduncular nucleus pro- 4-piperidinyl propionate; PPN-LDT, pedunculopontine-laterodorsal tegmental jection, projections of the pedunculopontine–laterodorsal tegmental complex; SMC, sensorimotor cortex; SPECT, single photon emission computed (PPN–LDT) complex, the parabigeminal nucleus, some medial vestibu- tomography; SUVR, standardized uptake value ratio; THAL, thalamus; VAChT, vesicular acetylcholine transporter; VER, vermis lar complex (MVC) neurons, and brainstem motor and autonomic 2884 © 2018 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/cne J Comp Neurol. 2018;526:2884–2897. ALBIN ET AL. 2885 neurons. BF cholinergic pathways participate in the modulation of To advance our understanding of the organization of cholinergic important cognitive functions such as attention and executive func- pathways in humans, we assessed the regional distribution of human tion (Ballinger, Ananth, Talmage, & Role, 2016; Hasselmo & Sarter, brain cholinergic neuron terminals with [18F]fluoroethoxybenzovesmi- 2011; Prado, Janickova, Al-Onaizi, & Prado, 2017). Projections of the col ([18F]FEOBV) positron emission tomography (PET; Aghourian PPN–LDT complex may play important roles in the regulation of sleep et al., 2017; Petrou et al., 2014). FEOBV is a high-affinity ligand for and waking, and some data implicates these neurons in control of bal- the vesicular acetylcholine transporter (VAChT), the protein responsi- ance and gait (Gut & Winn, 2016; Mena-Segovia & Bolam, 2017; Pie- ble for pumping ACh from the cytosol into synaptic vesicles (Prado naar, Vernon, & Winn, 2016). Striatal cholinergic interneurons are the et al., 2017; Prado, Roy, Kolisnyk, Gros, & Prado, 2013). VAChT is subject of intense investigations and play important roles in the con- expressed at uniquely high levels by cholinergic neurons (Arvidsson, trol of a variety of functions mediated by the striatal complex Riedl, Elde, & Meister, 1997). Prior human imaging studies of brain (Deffains & Bergman, 2015; Gonzales & Smith, 2015; Tanimura VAChT expression used less resolute single photon emission com- et al., 2017). puted tomography (SPECT) methods (Kuhl et al., 1994, 1996; Lamare Abnormalities of some of these pathways are implicated in neuro- et al., 2013). Prior PET studies of regional cholinergic terminal distri- logic and psychiatric disease, particularly Alzheimer disease (AD), Par- bution used acetylcholinesterase (AChase) substrates ([11C]methyl- kinson disease (PD), and tobacco abuse. Degeneration of the BF 4-piperidinyl propionate [PMP]; N-[11C]-methyl-4-piperidyl acetate complex is documented well in AD and PD, and degeneration of cho- [MP4A]) to identify cholinergic synapses (Iyo et al., 1997; Kuhl et al., linergic PPN–LDT neurons may drive important aspects of declining 1999). These methods are less specific. AChase, for example, is pro- gait and balance functions in PD and Progressive Supranuclear Palsy duced by midbrain dopaminergic neurons and high regional AChase (Bohnen et al., 2012; Gilman et al., 2010; Hirsch, Graybiel, Duyck- activity was detected in regions, the lateral cerebellar cortices, not aerts, & Javoy-Agid, 1987; Mesulam, 2013; Mufson, Ginsberg, Ikono- suspected to have substantial cholinergic terminal innervation movic, & DeKosky, 2003; Schliebs & Arendt, 2011). Augmenting (Greenfield, 1991; Kuhl et al., 1999). AChase enzyme activity may be cholinergic neurotransmission with acetylcholinesterase inhibitors is regulated by synaptic activity and disease states, a potential obstacle an accepted treatment for dementias, including AD, Lewy body to quantifying regional cholinergic terminal density (DeKosky et al., dementia, and PD-associated dementia. Anti-muscarinic cholinergic 1992). The very high AChase expression characteristic of the striatum agents are used for the treatment of dystonias and for treatment of limits quantification of striatal AChase as PMP and MP4A metabolite PD-associated tremor. Manipulations of cholinergic neurotransmission accumulation may be flow, rather than AChase activity, limited. PMP are being pursued to improve gait and balance functions in PD and MP4A are also, though to a considerably lesser extent, butyryl- (Chung, Lobb, Nutt, & Horak, 2010; Henderson et al., 2016; Kucinski, cholinesterase substrates and butyrylcholinesterase activity changes De Jong, & Sarter, 2017; Li et al., 2015). Nicotinic cholinergic recep- might influence the results of PET studies with these tracers (Snyder tors mediate the addictive effects of nicotine and drugs active at this et al., 2001). receptor family are used to treat nicotine addiction (Anthenelli et al., We describe the regional distribution of [18F]FEOBV binding in 2016). Improved understanding of the organization of cholinergic human volunteers with no evidence of neurologic or psychiatric dis- pathways in the human brain is relevant to efforts to expand useful ease. Our results largely confirm inferences from postmortem human cholinergic pharmacology in the treatment of human neurologic and studies and nonhuman mammal studies but indicate distinctive fea- psychiatric diseases. tures of human cholinergic pathways and indicate effects of aging. Prior investigations in other species, including nonhuman pri- mates, and work with postmortem human tissues provided consider- able information about the organization of human brain cholinergic 2 | METHODS pathways (Albin, Morgan, Higgins, & Frey, 1994; Barmack, Baugh- man, & Eckenstein, 1992; Barmack, Baughman, Eckenstein, & Shojaku, 1992; de Lacalle et al., 1994; De Lacalle, Hersh, & Saper, 1993; Emre, 2.1 | Subjects Heckers,
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